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| Status |
Public on Mar 13, 2015 |
| Title |
Study the transcriptional level changes of induced pluripotent stem (iPS) cells from X-linked Dyskeratosis Congenita (DC) Patients |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Dyskeratosis congenita is a bone marrow failure syndrome characterized by the presence of short telomeres at presentation. The X-linked form is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for in the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, suggesting induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we show that in iPS cells with DKC1 mutations Q31E, A353V and ΔL37 telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin varies, with recurrent mutation A353V showing the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by incorporation of a single copy of a wild type DKC1 cDNA into the AAVS1 safe harbor locus. None of the mutant cells show decreased pseudouridine levels in rRNA or defective rRNA processing. Finally transcriptome analysis of the iPS cells shows that WNT signaling is significantly decreased in all mutant cells, raising the possibility that defective WNT signaling may contribute to disease pathogenesis.
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| Overall design |
6 human iPS samples were investigated, including 1 WT sample (BMC) from health control, 2 duplicated samples Del371 and Del372 derived from DC patient with Del37mutation, 2 duplicated samples A353V1 and A353V2 derived from DC patient with A353V mutation, 1 sample Q31E derived from DC patient with Q31E mutation.
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| Contributor(s) |
Gu B, Apicella M, Mills J, Fan J, French D, Podsakoff GM, Bessler M, Mason PJ |
| Citation(s) |
25992652 |
| Submission date |
Mar 12, 2015 |
| Last update date |
Jun 12, 2015 |
| Contact name |
BAIWEI GU |
| E-mail(s) |
baiweigu@gmail.com
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| Organization name |
The Children's Hospital of Philadelphia
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| Street address |
3615 Civic center BLVD
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL5188 |
[HuEx-1_0-st] Affymetrix Human Exon 1.0 ST Array [probe set (exon) version] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA278084 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE66849_RAW.tar |
166.9 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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